Modular access to alkylgermanes via reductive germylative alkylation of activated olefins under nickel catalysis

Carbon-introducing difunctionalization of C-C double bonds enabled by transition-metal catalysis is one of most straightforward and efficient strategies to construct C-C and C-X bonds concurrently from readily available feedstocks towards structurally diverse molecules in one step; however, analogous difunctionalization for introducing germanium group and other functionalities remains elusive. Herein, we describe a nickel-catalyzed germylative alkylation of activated olefins with easily accessible primary, secondary and tertiary alkyl bromides and chlorogermanes as the electrophiles to form C-Ge and C-Calkyl bonds simultaneously. This method provides a modular and facile approach for the synthesis of a broad range of alkylgermanes with good functional group compatibility, and can be further applied to the late-stage modification of natural products and pharmaceuticals, as well as ligation of drug fragments. More importantly, this platform enables the expedient synthesis of germanium substituted ospemifene-Ge-OH, which shows improved properties compared to ospemifene in the treatment of breast cancer cells, demonstrating high potential of our protocol in drug development.

1.In the Figure 2, a broad scope of alkyl bromides was shown, how about other alkyl halides, such as alkyl chlorides and alkyl iodides? 2. In this manuscript, the authors demonstrated activated olefins having electron-withdrawing groups, such as acrylates could be tolerated well.What happens with other alkenes, such as styrenes.Getting other things to work would greatly strengthen the study.3. Ref. 8 and ref. 25 were the same.4. In the Figures 2-4, neither figure contains "a" labelling, but both captions contain text for "a". 5.In the SI, the "DMA" and "TDAE" were used in section 2 directly, which should be provided their full names to avoid confusing understanding.6. compounds 1bq and 1bs were missing of HRMS, if they are unknown compounds.7.In the section 3.2.1 General procedure of SI, it should provide a general equation, not a specialized one.Furthermore, the loading amount of alkene, germanium reagent and Mn powder in the main text should be modified, as well as the ligand should be deleted.
Reviewer #2: Remarks to the Author: In this manuscript Zhang and co-worker reported a synthetic protocol for alkylgermmane via a Nicatalyzed atom transfer radical addition and reductive coupling route.
Regarding the chemistry described here, current research is an extension of a well-established area of the chemistry of Ni-catalyzed ATRA and/or reductive coupling.A very similar example of such reaction route has been reported by the authors in this journal.The difference of the two reactions is the use of electrophile, chlorosilane for the previous one and chlorogermmane for the current one.Note that both chlorosilane and chlorogermmane are of very similar reactivity (oxidative addition) toward Ni(I), which have been reported by several groups in recent years.Furthermore, prior to the authors' works, examples for use of carbo-electrophiles (e.g.alkyl or aryl halides) in such Ni-catalyzed tandem transformations were also reported.
The major merit of this work is the synthetic efficiency and diversity for some organogermanes, especially for preparation of alkyl germane.Addition of germyl radical or anion species (e.g.germylmetal reagent) to electron-deficient alkenes usually led to beta-germylation.In this work, alpha-germylation is accomplished, which is complementary to known alkene germylation protocols.On the other hand, peralkylgermyl normally is difficult to be installed via an anion precursor since peralkylgermylmetal reagents are hard to be prepared so far.Recent reports show that peralkylgermane is a robust and easy-handling precursor for either carbo-anion or radical in some potentially useful synthetic transformations.Indeed, synthetic organogenmanium chemistry is rather less developed compared to those of organosilicon and -tin.In this regard, current work is useful for syntheses of some alkylgermmane derivatives and hence would be valuable for future research on organogenmanium reactions.
In general, this work might be of interest in the areas of organogenmanium chemistry, organogenmanium-mediated molecular transformations, and/or genmanium-centered functional/pharmaceutical molecules and hence might be published in this journal.
Technically, current work is solid, with an extensive examination of reaction scope and careful mechanistic study.However, the authors should also provide enough details for negative results, such as unreactive alkyl bromide and alkenes.For example, only one example was described for alphasubstituted acrylate (methyl).What happen with other substituents?Furthermore, what happens with beta-substituted acrylate (cis-or trans-, cyclic or acyclic, etc.)?What happen with other alkyl halides (e.g.iodide)?
Reviewer #3: Remarks to the Author: The paper by Prof Zhang, Bao and colleagues reports the synthesis of alkylgermanes via a nickelcatalysed germylative alkylation of electron-deficient olefins.The reaction enables the formation of a broad range of alkylgermanes from primary, secondary, or tertiary alkyl bromides, different activated alkenes (i.e., bearing ester, amide, cyano, sulfone, phosphonate moieties) and chlorotrialkylgermanes, in the presence of nickel bromide and manganese.The scope of the reaction seems to be broad, encompassing a wide range of substituents and useful functional groups.Examples of functionalisation of the synthesised alkylgermanes have been reported.A number of control experiments to investigate the reaction mechanism have been performed and a reasonable hypothesis of mechanism is provided.The potential synthetic utility of the described protocol is studied by its application to the late-stage functionalisation of pharmacologically relevant molecules, including ospemifene, which demonstrated interesting bioactivity in the prevention of breast cancer, behaving as Selective Estrogen Receptor Moldulator (SERM).
In my opinion, dealing with the development of a new route towards functionalised and functionalisable germanium-containing molecules, the results described in the study could meet the interest of a broad range of organic chemists.The versatility of organogermanes in organic synthesis and their potential application as bioisosteres of carbon-analogues in medicinal chemistry render this work attractive for a broad readership.On the basis of these consideration, I feel that this paper can be suitable for publication in Nat.Commun.after revision.In my opinion, there are several points that should be addressed before accepting the manuscript for publication (see below).

About the synthetic part:
-During the optimisation of the reaction conditions, the authors reported interesting yields using the chiral bisoxazoline ligand (L5); see for example entry 6 of Table 1.However, this reviewer could not find any data on the stereochemical outcome of the reaction in the presence of the chiral ligand.Is compound 4 formed as a racemate?Enantioselective HPLC (or SFC) should be performed on the alkylgermane 4. The possibility to develop an enantioselective approach towards alkylgermanes would significantly enhance the impact of the work.
-Lines 180-181: "to construct germamium-containing all-carbon quaternary stereogenic center 40-45…".Please, consider the structure of the mentioned and revise the sentence."all-carbon quaternary stereogenic center" is not correct.-In the supplementary information file, the scale of all provided NMR spectra should include the 'zero' (zero ppm).

About the biological part:
The authors reported a study on the antiproliferative activity of ospemifene and a germanium-containg related compound (71) against MCF-7 (ER+) and MDA-MB-231 (ER-) human breast cancer cell lines using MTT assay.The metabolic stability of 71 was also explored and compared with that of ospemifene by mouse liver microsomal metabolic assay.The hemocompatibility of the germaniylderivative of ospemifene was also assessed.Globally, the obtained results are encouraging and, although 71 exhibited only a moderate improvement in IC50 values with respect to ospemifene against MCF-7 (ER+) cell line, the functionalisation of the ospemifene structure seems to be related with improved pharmacological properties.However, although the preliminary findings reported are promising, additional studies should be performed to highlight some important points.
-The toxicity of compound 71 against normal human cell lines (breast, liver, etc.) should be evaluated and compared with that of ospemifene.
-Although ospemifene is an achiral molecule, compound 71 possesses a stereogenic center.The activity of the ospemifene-derivative 71 has been investigate on the racemate; however, the biological properties of the two enantiomers of 71 can be significantly different.This point needs to be addressed by assessing the biological properties of the two enantiomers of 71.Separation of racemate 71 should be accomplished (for example by enantioselective HPLC) and the antiproliferative properties of the two enantiomers against MCF-7 (ER+) and MDA-MB-231 (ER-) cells -as well as cytotoxicity studies against normal cells -should be investigated.
-The structure of 71 differs from ospemifene not only for the presence of the germanyl substituent.Is there any data on the antiproliferative data of the coupound that could be prepared through protodegermanation of 71? Please, avoid using terms such as "great yields".Stereochemistry indicators (R, S) should be italicised (i.e., line 207).
The English form should be revised as there are some typing/grammar mistakes throughout the text.

Reviewer: 1
Recommendation: 'Therefore, I'm happy to recommend the publication of manuscript in Nat.Commun., after some revisions were addressed.'

Comments:
1.In the Figure 2, a broad scope of alkyl bromides was shown, how about other alkyl halides, such as alkyl chlorides and alkyl iodides?
Response: Thanks for your comments.We selected 1-chloro-3-phenylpropane and 1-iodide-3-phenylpropane as the substrates for the germylative alkylation with 2a and 3a under standard conditions, which gave desired products in 0% and 52% yields, respectively.These results indicate that alkyl chlorides are inert, but alkyl iodides are reactive in this protocol.The related data has been added in the revised manuscript and the supplementary information.
2. In this manuscript, the authors demonstrated activated olefins having electronwithdrawing groups, such as acrylates could be tolerated well.What happens with other alkenes, such as styrenes.Getting other things to work would greatly strengthen the study.Response: Thanks a lot for your kind suggestions.Several different types of olefins including styrene, α-substituted acrylate, β-substituted acrylates and unactivated terminal alkene were tried, and the results demonstrated that only α-substituted acrylate is compatible in current system, which gives the desired product in 67% yield (entry 4 of following table).The related data has been added in the revised manuscript and the supplementary information.